The field of the invention is nuclear magnetic resonance imaging methods and systems. More particularly, the invention relates to imaging the lungs using a noble gas such as Helium-3 or Xenon-129.
Lung disease, which includes asthma, chronic obstructive pulmonary disease (COPD), tuberculosis, and influenza is a significant and growing public health issue. In the year 2003, chronic lower respiratory disease was the fourth leading cause of death in the United States, claiming the lives of over 126,000 Americans. In contrast to mortality rates for cancer and heart disease—America's two leading causes of death, both of which decreased between 1979 and 1998—lung disease rates increased by 19.3 percent over the same interval. Not only are some lung diseases fatal, they are also chronic, affecting over 35 million Americans. Asthma and COPD account for approximately one in five cases of depression and reduced general health. Asthma affects almost 10% of the United States population, is the leading cause of pediatric hospitalizations, and has doubled in prevalence since 1980. Lung disease has a profound economic impact, costing over $141.8 billion a year in direct and indirect treatment related costs.
Within the spectrum of lung disorders, obstructive lung disease, which includes asthma and COPD, is of particular concern, accounting for approximately 35.2% of all lung related deaths in the year 2000. The mechanical properties of lung parenchyma have a fundamental role in the pathophysiology and natural history of these diseases. However, current methodologies are incapable of directly measuring these changes in vivo.
The distinct biological processes that underlie asthma and COPD, which are manifested in the macroscopic mechanical properties of lung parenchyma are not accessible by standard PV measurements. While asthma and COPD have distinct pathophysiologies, both processes produce end expiratory air trapping within the acinar units of the lung. In the asthmatic, airway smooth muscle activation, in response to a pro-inflammatory stimulus, remains central in the pathophysiology of the syndrome and it is now appreciated that 1) tissue-constriction need not be confined to the airways but may also involve contractile elements of the lung-parenchyma; 2) mucosal swelling and luminal secretions contribute significantly to reduced flows in peripheral airways; 3) peribronchial fibrosis and airway remodeling are a major cause of reduced flows in chronic asthma; and 4) all these mechanisms account to varying degrees for the large heterogeneity in regional volumes, ventilation, and mechanical properties. In COPD, while local destruction of alveoli produces a loss of parenchymal elasticity and airway enlargement, it is also appreciated that this process results in remodeling of connective tissue elements, most notably collagen, resulting in changes in the mechanical properties not only of parenchyma but also conductive airways.
Loss of tissue elasticity, particularly around airways, compromises their patency, precipitating end expiration collapse and regional air trapping. Thus, asthma and COPD present a dilemma: while both induce end-expiratory air trapping, the same volumetric condition is arrived at through dramatically different states of the mechanical properties of lung parenchyma. In asthma parenchymal stiffness remains relatively unaffected. In contrast, COPD will induce a decrease in parenchymal stiffness as a result of alveoli destruction and connective tissue element remodeling. Although changes in the expiratory phase of the quasi-static pressure-volume (PV) curve provide global insights into volumetric changes within the lung, these data cannot quantify regional pre-stress conditions which could potentially distinguish between a state of hyper inflation of normal (or asthmatic) and normally inflated emhypsemic parenchyma.
Spirometry provides a global measure of lung and airway properties. While repeated spirometry can provide insight into the volatility of the bronchi, the technique does not quantify remodeling induced changes in airway plasticity, is limited by its global nature (lacks spatial specificity), and is relatively insensitive to changes in small airway structure and function. Sputum monitoring and respiratory tests before and after the administration of bronchial dilators to assess changes in airway plasticity impose similar constraints by providing global and, at best, indirect information on spatial extent. Breath-held high speed computed tomography (CT) enables a direct visualization of the lung tissue. Unfortunately, its spatial resolution is insufficient to characterize structure and dynamics of high generation airways that are subject to remodeling. CT does provide a topographical map of gray scale distributions that may be viewed as surrogates of regional volume but regional volume information does not provide regional mechanical information and may not inform about airway remodeling. Thus CT does not differentiate between disease induced pre stress conditions arising from emphysema, asthma, and others.
Many magnetic resonance imaging (MRI) techniques have been proposed for imaging the lungs using a paramagnetic gas. A noble gas such as Xenon-13 or Helium-3 is inhaled into the lungs prior to the MRI scan to increase SNR of the acquired image. The noble gas is thermally or equilibrium polarized and is preferably hyperpolarized to produce a strong NMR signal when excited at its Larmor frequency. Imaging methods that employ paramagnetic gases are disclosed, for example, in U.S. Pat. Nos. 5,789,921; 6,241,966; 6,338,836; 6,370,415; 6,589,506 and in published U.S. Pat. Appln. Nos. 2001/0031242; 2002/0043267; 2002/0198449; 2003/0023162 and 2004/0260173.
While magnetic resonance imaging using RF tagging techniques have also been suggested as a method for assessment of the mechanical properties of parenchyma this approach is limited to assessing the change in lung volume throughout the respiratory cycle and does not assess the intrinsic mechanical properties of parenchyma. Tagged MR images of the lung will only elucidate regional changes in parenchyma inferring rather than actually measuring the intrinsic mechanical properties of parenchyma.
It has been long known that lung parenchyma exhibits elastic properties that can be quantitated by K and μ and that these parameters describe uniform inflation and isovolume deformation respectively. Ex vivo animal studies have demonstrated that in normal lungs, both K and μ are linearly related to transpulmonary pressure, Ptp and that both parameters increase with age. In obstructive lung disease, it is generally accepted that not only the type but also the spatial distribution/heterogeneity of disease affect the intrinsic mechanical properties of lung parenchyma. Within the asthma model, both the parenchymal bulk and shear moduli have been reported to increase with bronchoconstriction in rat lung, suggesting that parenchyma stiffness should increase with asthma severity. Simulation studies have also identified the relationship between airway patency and the mechanical properties of parenchyma pointing to the relationship between regional air trapping and stiffness. Using a monoexponential model to describe the expiration phase of the respiratory PV curve, significant differences have been demonstrated in the PV curves for normal, emphysemateous, and fibrotic lungs. Because it is generally accepted that the shear modulus of lung parenchyma is related to Ptp according to the relationship, μ≅0.7 Ptp then disease induced changes in the PV curve translate directly to changes in the mechanical properties of lung parenchyma.
It has been found that MR imaging can be used to image the mechanical properties of tissues when an oscillating stress is applied to the object being imaged in a method called MR elastography (MRE). The method requires that the oscillating stress produce shear waves that propagate through the organ, or tissues to be imaged. These shear waves alter the phase of the NMR signals, and from this the mechanical properties of the subject can be determined. In many applications, the production of shear waves in the tissues is merely a matter of physically vibrating the surface of the subject with an electromechanical device such as that disclosed in U.S. Pat. No. 5,592,085. For example, shear waves may be produced in the breast and prostate by direct contact with the oscillatory device. As discussed in U.S. Pat. No. 5,825,186, images can be reconstructed from the acquired MRE data in which the brightness of individual pixels therein are modulated, or weighted by the stiffness of the corresponding tissue.